Influence of acute and chronic kidney failure in rats on the disposition and pharmacokinetics of ZYAN1, a novel prolyl hydroxylase inhibitor, for the treatment of chronic kidney disease-induced anemia.

1. ZYAN1 is a prolyl hydroxylase inhibitor in clinical development for treatment of anemia associated with chronic kidney disease (CKD). We evaluated the effect of acute and chronic kidney impairment on the pharmacokinetics of ZYAN1 in rat models. 2. Cisplatin (2.5, 5 and 7.5 mg/kg) was used to induce acute kidney injury (AKI), and five-sixth and total nephrectomy was used to induce chronic kidney injury (CKI) in male Wistar rats. All groups received a single 15 mg/kg oral dose of ZYAN1. Blood/urine samples were analyzed for ZYAN1 to assess peak concentration (Cmax), area under the concentration-time curve (AUCinf), total body clearance (CL/F) and elimination half-life (T1/2). 3. Cmax and AUCinf were not significantly different in the various AKI groups or in five-sixth nephrectomized rats, as compared to control rats. Recovery of ZYAN1 in urine was reduced; the impact on the CL/F was minimal. There was a 2-fold increase in AUCinf with reduction in CL/F in total nephrectomized rats. T1/2 was longer for ZYAN1 in the severe AKI/five-sixth nephrectomy rats and total nephrectomy rats as compared to control rats. 4. Based on the rodent data it may be inferred that PK of ZYAN1 in CKD patients may be minimally affected.

A sensitive assay for ZYAN1 in human whole blood and urine utilizing positive LC-MS/MS electrospray ionization.

AIM: A sensitive LC-MS/MS method was developed and validated for estimation of ZYAN1 in human blood/urine. METHODS: An analog internal standard IOX2 along with ZYAN1 was quantified using selective reaction monitoring in positive mode. The chromatographic separation was performed by gradient elution with C18 analytical column (3 µm, 50 mm × 2.0 mm) with 4-min run time using an acidified mobile phase consisting of ammonium formate and acetonitrile. Protein precipitation enabled extraction of analytes from diluted blood/urine. RESULTS: Calibration curve of ZYAN1 was linear (2-5000 ng/ml). The recovery of ZYAN1 and IOX2 was between 87 and 104%. Interday and intraday accuracy and precision was found well within the acceptance criteria. CONCLUSION: The validated assay was applied for clinical pharmacokinetics of ZYAN1 in healthy volunteers.